Tetracycline sulfamate and derivatives thereof



United States Patent Int. (:1. c07c 103/19 US. Cl. 260559 6 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:

T- (RNHSO H) wherein T is tetracycline or an administratable therapeutically active derivative thereof, R is a linear alkyl group of 2 to 18 carbon atoms and n is 1 or 2. Therapeutic compositions comprising these compounds and a pharmaceutically acceptable carrier have an excellent local tolerance for all modies of administration, including oral, parenteral, rectal and topical. Beneficial results are illustrated with tetracycline n-dodecylsulfamate and tetracycline n-hexylsulfamate. The compounds are prepared by reacting an n-alkylsulfamic acid with a tetracycline in a slightly warm alcoholic solution.

The present invention relates to new tetracycline derivatives. More particularly, it relates to antibiotic medicameters or drugs having an excellent local tolerance for all methods of administration. Even more particularly, the invention relates to tetracycline sulfamate derivatives and to pharmaceutical compositions made therefrom.

The tetracyclines constitute essentially the most widely used group of antibiotics for therapeutic purposes. Their wide antimicrobial spectrum permits their use for the efficacious treatment of a considerable series of infectious diseases.

These products are easily absorbed upon oral administration, however, their systematic use by this mode of administration can cause considerable inconveniences, among which are the manifestation of intestinal superinfections, avitaminosis K and frequent gastrointestinal intolerances such as vomiting and diarrhea.

The use of related derivatives is therefore of consider able interest. However, compositions prepared from tetracycline derivatives are often poorly tolerated upon intramuscular administration, their absorption being less complete and inconsistent. Hypodermic administration and intravenous administration are hence less favorable with such compositions.

Accordingly, one of the objects of the present invention is to provide a new series of tetracycline derivatives which avoid the disadvantages of the prior art tetracyclines.

Another object of the present invention is to provide a process for the preparation of tetracycline sulfamate derivatives which may be carried out in an effective and advantageous manner.

Still another object of the present invention is to provide pharmaceutical compositions comprising n-alkylsulfamates of tetracycline and derivatives thereof which have an excellent local tolerance for all modes of administration.

A further object of the invention is to provide pharmaceutical compositions comprising novel tetracycline derivatives having advantageous solubility properties, good stability and, as desired, an immediate and intense effect or a prolonged effect.

ICE

Yet another object of the present invention is the provision of the administration of thhe novel tetracycline derivatives described herein by various routes to achieve excellent therapeutic eifects.

These and other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of the following specification and claims.

In accordance with the present invention, it has been found that tetracycline n-alkylsulfamates or derivatives thereof having the general formula wherein T is a tetracycline molecule or a therapeutically acceptable derivatives thereof containing the tetracycline nucleus and having an antibiotic activity, R is a linear alkyl radical having from 2 to 18 carbon atoms and n is 1 to 2, are effective as excellent antibiotic drugs having a good local tolerance for all methods of administration.

The active constituents of the medicament of the present invention are characterized by a good solubility in organic solvents, particularly in alcohols and glycols. The solubility thereof in water varies according to the length of the alkyl chain and the particular tetracycline moiety present in the molecule, but for any given tetracycline compound the solubility in water of the alkyl sulfamate derivatives decreases as the number of carbon atoms in the alkyl group increases. Thus, a series of compounds may be provided which pass from a perfect solubility to one which is practically zero. This fact together with the good stability of the novel compounds of the present invention makes it possible to utilize the same advantageously in pharmaceutical compositions in accordance with the desired object of, for example, having either an immediate and intense efiFect or, on the contrary, in preparations where a prolonged effect is sought.

The novel tetracycline compounds of the present invention may be prepared by reacting an n-alkylsulfamic acid with the desired tetracycline molecular in an alcoholic slightly warm solution until the two reagents are completely dissolved. The desired product is formed thereby and may be isolated by conventional means, for example, by evaporating the solvent at reduced pressure or by precipitation by adding to the reaction medium a slightly polar solvent in which the tetracycline n-alkylsulfamate formed is insoluble.

The alcohol utilized as reaction medium is preferably ethanol, or anhydrous ethanol, or isopropanol. The reaction is generally carried out at a temperature of about 30 to 60 C. The precipitation medium most often employed is ethyl ether, anhydrous isopropyl ether or petroleum ether. In certain instances, mixtures thereof may be employed.

In order to isolate the novel compounds from the alcoholic solution thereof, in addition to the methods indicated hereinabove, a preferred process in certain cases is to nebulize, i.e., to pulverize the alcoholic liquid into fine particles, and then to evaporate the solvent by introducing the particles into a hot gaseous stream.

Another method of preparation, starting from the same n-alkylsulfamic acids and the corresponding tetracyclines, comprises preparing in situ an aqueous solution of an alkaline metal or ammonium n-alkylsulfamate containing from 2 to 18 carbon atoms by directly neutralizing the acids with the desired base and putting this solution into contact with an aqueous solution of the corresponding tetracycline in the form of a mineral acid salt which may equally be prepared, if necessary, prior to the neutralization reaction. The desired tetracycline alkylsulfamate is then isolated by filtration, washed and dried at reduced pressure, at moderate temperatures and in the presence of phosphoric anhydride.

The temperature which is required for the reaction is essentially determined in each case on the basis of the solubility of the n-alkylsulfamates in water since, the longer the alkyl chain, the less soluble the salt, and the higher will thus be the temperature necessary for causing it to pass into solution. Inview of, on the one hand, the risk of thermal decomposition of the tetracyclines and, on the other hand, the solubility in wateralready mentioned hereinaboveof the tetracycline alkylsulfamate having a shorter alkyl chain, this modified embodiment is not advantageous when compounds located at the two ends of the series are being prepared.

The two reagents are utilized in practically stoichiometric quantities. The proportion is equimolecular in case the tetracycline employed is monobasic, such as with tetracycline itself, chlortetracycline, oxytetracycline, methylene-oxytetracycline or demethylchlortetracycline. Two moles of alkaline metal or ammonium n-alkylsulfamate or of free acid (n-alkylsulfamic acid) are used per one mole of the corresponding tetracycline, present in the form of a mineral acid salt or in the form of a free base, in the case where the tetracycline derivative contains a supplementary basic group, such as, for example, in n-(2-hydroxyethyl)-diethylenediaminomethylenetetracycline, pyrrolidinomethylenetetracycline or tetracycline- L-methylenelsine.

The n-alkylsulfamic acids and the alkaline or ammonium salts thereof used as starting materials may be obtained by processes known in the art, detailed example of which are given hereinbelow.

The n-alkylsulfamates of tetracycline thus obtained generally have an excellent degree of purity but, if necessary, they may be subjected to a supplementary purification which consists normally in dissolving them in an alcoholic solvent or in acetone and in precipitating them by means of a slightly polar medium, such as ethyl ether or anhydrous isopropyl ether.

The following examples are given merely as illustrative of the preparation of the novel tetracycline derivatives of the present invention and are not to be considered as limiting. Unless otherwise noted, the percentages therein are by weight.

EXAMPLE 1 Added to a solution of 121.5 grams (1.2 moles) of nhexylamine in 500 cc. of chloroform, dropwise and while stirring vigorously, is a solution of 46.7 grams (0.4 mole) of chlorosulfonic acid in 150 cc. of chloroform in a flask equipped with a refrigerant and protected against the ambient humidity. Stirring is continued for -30 minutes, and the solution is then extracted with 500 cc. of 2 N soda (sodium carbonate). Added to the aqueous layer, which is freed from residual chloroform by evaporation at reduced pressure, is sulfuric acid at 50% by weight per volume up to the complete precipitation. The crystals obtained are washed with water (2 or 3 times with 10-15 cc. each time), and the operation is concluded by drying in vacuo in an oven at 60 C.

Obtained are 36.8 grams (a theoretical yield of 50.7%) of n-hexylsulfamic acid in the form of crystals in chips. They are soft to the touch, not very soluble in cold water, soluble in hot water, soluble in aliphatic alcohols, moderately soluble in chloroform and very slightly soluble in ethyl ether. The melting point thereof is 140-143 C. (Kofier). The infrared spectrum (KBr pastille) gives the following representative bands: 2.32; 3.4; double band at 9.25 and 9.3; 12.95; 13.9; large intense band toward 8,.

Upon titration with 0.1 N soda (sample dissolved in methanol) in the presence of phenolphthalein, a content of 100.3% is found.

18.13 grams (0.1 mole) of n-hexylsulfamic acid obtained as described above is dissolved in 200 cc. of absolute ethanol at 45 C. Added to the solution thus obtained is 44.44 grams (0.1 mole) of basic anhydrous tetracycline,

or the equivalent amount of partially hydrated product, while vigorously stirring, up to the complete dissolution thereof. The stirring action and the temperature are maintained for 15-20 minutes. Then, the reaction mixture is allowed to cool to ambient temperature, and the reaction mixture is poured while stirring into 6-7 times its volume of ethyl ether. The precipitate formed is either filtered or decanted, washed by trituration with petroleum ether or hexane, filtered and dried for several hours at reduced pressure, preferably at a temperature of 40-45 C.

Obtained is 53.2 grams (a theoretical yield of of tetracycline n-hexysulfamate in the form of a light yellow powder. It is soluble in Water, in aliphatic alcohols and in glycols and insoluble in ethyl ether, petroleum ether and hexane. The melting point thereof is 153-159 C. with decomposition (Kofier) (acetonezether). The pH value of a 3% solution in distilled water is about 2.4. The infrared spectrum (KBr pastille with the incorporation of alcohol up to dryness) is as follows: principal maximums 3.05; 3.4; 6.4; 6.95; 8.2; 8.5; double band at 9.45 and 9.6

Elementary analysis. Found (percent): N=6.63; S=4.95.

Analysis-calculated for C H N O S (percent): N=6.71; S=5.12.

Bacteriological capacity (relative to the tetracycline hydrochloride.Diffusion method: 758; 765 ,ug./mg. Theoretical capacity: 768.5 gjrng.

EXAMPLE 2 33.5 grams of n-hexylsulfamic acid is added while stirring to 250 cc. of absolute ethyl alcohol, and the mixture is heated to 40-45 C. up to complete dissolution. 82.1 grams of anhydrous tetracycline base is then added while the stirring is continued, and the temperature is held up to the complete dissolution. The reaction is al lowed to continue for another 30 minutes. The solution is freed from impurities by filtration. Then, evaporation is carried out at reduced pressure up to dryness. The product obtained is triturated and dried in an oven in vacuo at 50-60 C. for several hours.

Obtained is 114 grams (a theoretical yield of 98.5%) of tetracycline n-hexylsulfamate having the same characteristics as the product obtained in accordance with Example 1.

EXAMPLE 3 5.30 grams (0.02 mole) of n-dodecylsulfamic acid is dissolved in cc. of 0.2 N soda at 50-60 C. The sOlution is subjected to an intense stirring while a solution of 9.62 grams of tetracycline hydrochloride in cc. of water is added thereto dropwise. Stirring is effected for 20 minutes at 5060 C. Thereafter the liquid of the precipitate formed is decanted and the latter is washed by returning it into suspension in 200 cc. of water. The reaction solution is then filtered and the obtained cake is washed twice with 50 cc. of water. It is then dried in an oven in vacuo at 60 C. in the presence of phosphoric anhyd'ride.

Obtained is 12.6 grams (a theoretical yield of 89%) of tetracycline n-dodecylsulfamate in the form of a light yellow powder. It is practically tasteless, very slightly soluble in water, soluble in ethyl alcohol, isopropanol, propylene glycol, acetone and in hot chloroform, almost insoluble in ethyl ether and insoluble in petroleum ether and hexane. The melting point thereof is 133-140 C. (acetone petroleum ether) The infrared spectrum (KBr pastille with the incorporation of alcohol) gives the following principal maximums: 3.05; 3.42; 3.5; 6.22; 6.35; 6.9; 8.2; 8.4 and a double band at 9.67 and 9.76

Elementary a/zalysis.Found (percent): S=4.45

5 Analysis.-Calculated for C I-I N O S (percent): N=5.94; S=4.51.

Bacteriological capacity (relative to the tetracycline hydrochloride). Ditfusion method: -670 ,ug./mg. Theorectical capacity: 677 ,ug./mg.

EXAMPLE 4 Placed in suspension at 35-40 C. While stirring is 32.15 grams (0.1 mole) of n-hexadecylsulfamic acid in 300 cc. of absolute ethanol. Added to the mixture is 44.44 grams (0.1 mole) of anhydrous basic tetracycline or the equivalent of partially hydrated product until the two reagents are solubilized. Stirring is continued and the temperature is maintained for 20-30 minutes, and the solvent is then evaporated to dryness at reduced pressure. Trituration and drying in an oven at 5060 C. in a vacuum less than 1 mm. [Hg] are then carried out.

Obtained is 74.3 grams (a theoretical yield of 97.0%) of tetracycline n-hexadecylsulfamate. It is a light yellow powder which is tasteless, insoluble in water, soluble in aliphatic alcohols, acetone and chloroform, slightly soluble in ethyl ether and insoluble in petroleum ether.'

The melting point of the product is 132-136 C. (Kofler). The infrared spectrum (KBr pastille, drying with alcohol) presents the same band as those of the dodecylsulfamic homologue, but with different relative intensities.

Elementary analysis.-Found (percent): S=4.01.

Analysis.Calculated for C H N S (percent): N=5.49; S=4.18.

Bacteriological capacity (relative to the tetracycline hydrochloride).Ditfusion method: 612 ug/mg. Theoretical capacity: 628 ,ug./mg.

EXAMPLE In accordance with the process described in Example 4, 321.5 grams (0.1 mole) of n-hexadecylsulfamic acid is dissolved in 3,000 cc. of isopropanol. Added there is 444.4 grams (1 mole) of anhydrous base tetracycline so as to obtain a solution of tetracycline n-hexadecylsulfamate in isopropanol. The solution obtained is nebulized.

Obtained thereby is 705 grams (a theoretical yield of 92%) of tetracycline hexadecylsulfamate having the same characteristics as the product obtained according to Example 4, but with a lower apparatus density.

In accordance with analogous processes, the alkylsulfamates of other derivatives of tetracycline, such as, for example, oxytetracycline, chlortetracycline, methyleneoxytetracycline, demethylchlortetracycline, pyrrolidinomethylenetetracycline, N-(2-hydroxyethyl) diethylenediaminomethylenetetracycline, and tetracycline-L-methylenelysine, may be obtained. For the three last-mentioned derivatives, the proportion of reactants used is 2 moles of alkylsulfonic reagent per mole of tetracycline compound.

Toxicological, pharmacological and clinical tests will now be indicated hereinbelow, exclusively by way of nonlimitative examples, which were effected on two compounds forming the active constituent of the pharmaceutical preparations of the present invention. Specifically, tetracycline hexylsulfamate and tetracycline dodecylsulfamate were used in the tests since they are perfectly representatve of the compounds of the series.

( l) Toxicity (a) Acute toxicity-The LD determined for mice by the oral method is greater than 2 g./kg. for the two compounds tetracycline hexylsulfamate and tetracycline dodecylsulfamate. By the intraperitoneal method, it is approximately 3l0.2 mg./kg. for tetracycline dodecylsulfamate and about 380.6 mg./kg. for tetracycline hexylsulfamate; for tetracycline hydrochloride, according to the same technique, about 220.5 mg./kg. is found.

(b) Subacute toxicity.--The tests which were effected show a good general tolerance both for tetracycline dodecylsulfamate and tetracycline hexylsulfamate. The equivalent of 50 mg./kg. per day of these compounds was administered to 6 male rabbits for 30 days and was well tolerated (this being a dosage greater than the therapeutic dosage which is 10-25 mg./kg./ day).

(2) Spectra of activity These have been determined by the method of dilutions on a great variety of germs, and it has been found that there are no appreciable differences between the activity spectra of the two compounds of the present invention and other forms of tetracycline, the antibiotic properties thus being preserved.

(3) Tolerance and asbosption DifiFerent tests effected with the two compounds show a good tolerance by rabbits for the intramuscular method.

In order to determine in a more precise fashion the local tolerance and the absorption, the following method was used:

(a) A solution is prepared containing 250 mg. of tetracycline activity in 4 cc. of solvent.

(b) 0.2 cc. per animal (white rat) is injected at the rate of 10 animals per experiment and per compound. The injection is carried out subcutaneously in the abdomen.

(c) Five animals of each group are sacrificed at the end of 5 hours, and the other five at the end of 20 hours after injection.

(d) The skin of the abdomen is dissected and a macroscopic study of the subcutaneous tissue is elfectd by taking as reference the following notes:

Local tolerance- 0=absence of lesion l=vascular injection 2=hemorrhage 3=necrosis Absorption- 0=absence of deposit l=slight deposit 2=moderate deposit 3=significant deposit.

The following formulas were tested:

The weights are taken according to the respective equivalence in tetracycline activity.

The results obtained are compiled in Table I.

TAB LE I Absorption Tolerance (deposit) 5 hours 20 hours 5 hours 20 hours Formula:

The figures indicated in Table I represent the average of the results that have been obtained and show the superiority of tetracycline hexysulfamate and of tetracycline dodecylsulfamate, both with respect to the good tolerance and the absorption thereof.

(4) Hematic concentrations (a) Oral administration.-Administered to groups of 10 rats, each weighing about 150 grams, were doses (expressed in tetracycline activity) of 50 mg./kg. of tetracycline dodecylsulfamate, tetracycline hexysulfamate and tetracycline hydrochloride, respectively. One group was sacrificed for each product 1, 3, 5 and 7 hours, respectively, after the administration while the blood levels were determined. The results are indicated in Table II in the form of mean values expressed in ,ug./ 0111.

TABLE II Concentration, [.LEJCHL at the end of- Product 1 hour 3 hours 5 hours 7 hours Tetracycline dodecylsulfamaten 2. 1 1. 6 0. 9 0. 7 Tetracycline hexylsulfamate 2.4 1. 8 1 0. 7 Tetracycline hydrochloride- 1. 6 1. 1 0. 6

TABLE III Concetnration g./ cmfiat the end ot Product 2 hours 7 hours Tetracycline dodccylsulfamate 4. 8 3. 1 Tetracycline hexylsuliamate 136(2) Mepieycline The hematic levels obtained according to this method are clearly superior to those of mepicycline, the tolerance being very good.

Intramuscular administration.'I'hree tests were carried out on rabbits, using 3 groups of animals. Administered to them, respectively, were tetracycline dodecylhydrochloride in solution form containing 50 mg. of prod uct to be tested (expressed in tetracycline hydrochloride) per cc. of solvent and per kg. of weight.

Hematic evaluations were made at the end of 2, 10, 15 and 20 hours, respectively, and the values were deduced by interpolation on a normal curve of tetracycline hydrochloride.

The experiment was repeated in intervals of 8 days, changing the groups of animals in such a manner that each group received each of the products once.

No variations in the groups used were noted, and Table IV gives the average of the results obtained.

TABLE IV Concentrations gJcmfi at the end of- Product 2 hours 10 hours 15 hours 20 hours Tetracycline dodecylsulfamate 6. 3 5. 8 7. 2 2 5. 4 5. 2 6. 1 1. 5

Tetracycline hexylsuliamate. 5. 8 6. 1 8. 2 2. 3 5. 4 5. 2 8. 0 1. 2

Tetracycline hydrochloride. 4. 2 5. 3 3. 8 3. 7 5. 9 4. 1

1 Not detectable.

The results which were obtained confirm that a slow and constant absorption takes place both for tetracycline dodecylsulfamate and tetracycline hexylsulfamate. The concentrations obtained are superior to those of tetracycline hydrochloride in such a manner that, in view of the excellent tolerance of the two compounds, both of them are good antibiotics with a prolonged action.

(5) Clinical tests The products were used in 301 cases having diiferent infectious syndromes, by the intramusclar method and orally, under the following conditions.

Tetracycline dodecylsulfamate Intramuscular method: Cases 500 mg. every 12 hours 23 '250 mg. every 12 hours 41 mg. every 12 hours 28 Oral method:

250 mg. every 8 hours 20 Tetracycline hexylsulfamate Intramuscular method:

500 mg. every 12 hours 37 250 mg. every 12 hours 52 100 mg. every 12 hours 26 Oral method:

250 mg. every 8 hours 74 The tolerance relative to the intramuscular method is very good in all of the cases, including those with the highest doses. Adverse effects after the ingestion of the medicine orally were not observed either. Noted were a good delayed efiect and a good therapeutic eflicacy. The medicine proposed by the present invention may be administered orally, rectally or parenterally in doses of between 100 and 1000 mg. of active constituent every 24 hours (expressed as tetracycline hydrochloride).

For these forms of administration, the medicine is available in the form of injectable ampoules, capsules, syrups or suppositories with the appropriate excipients.

Six pharmaceutical formulas of the medicine according to the present invention will be given hereinbelow by way of non-limitative example.

(A) Tetracycline dodecylsulfamate (1) Injectable preparation 100:

9 As solvent the following are utilized:

Percent Dimethylacetamide 12.5 Benzyl alcohol 2.5 Glyceryl formal 15 Lidocaine 1 H O, quantity sufiicient for 100% in the amount of 2.5 cc. for preparation 100 and 4 cc. for preparations 250 and 500.

(4) Capsules:

Tetracycline dodecylsulfamate gram 0.368 Mg stearate do 0.020 Excipient (amidon or lactose), sufiicient quantity.

(5) Syrup:

Propylene glycol cc 20 Tetracycline dodecylsulfamate g 2.25 Tween 20 (polyoxyethylene sorbitan monolaurate) g 2.0

Saccharine soluble g 0.2 Sodium cyclamate g 1.5 Vitamin C g 3.0 40% sodium bisulfite cc 0.2 70% sorbitol cc 2.5 Essence of currant mg 0.5 Water, quantity suflicient for 60 cc.

(6) Suppositories:

Tetracycline dodecylsulfamate g 0.147 Excipient (Monoleno IM 8) g 1.400

(7) Suppositories:

Tetracycline dodecylsulfamate g 0.368 Excipient (Monoleno IM 8) g 1.150 (8) Suppositories:

Tetracycline dodecylsulfamate g 0.737 Excipient (Monoleno IM 8) g 1.850

(B) Tetracycline hexylsulfamate (1) Injectable preparation 100:

Tetracycline hexylsulfamate g 0.130 Sodium glycinate g 0.050 NaHSO g 0.013 Ampoule- Lidocaine hydrochloride g 0.025 Propylene glycol g 0.100 Polysorbate 80 (polyoxyethylene sorbitan monooleate) g 0.050 Water, quantity suflicient for 2.5 cc. (2) Injectable preparation 250:

Tetracycline hexylsulfamate g 0.325 Sodium glycinate g 0.100 NaHSO g 0.022 Ampoule Lidocaine hydrochloride g 0.040 Propylene glycol g 0.200 Polysorbate 80 g 0.100 Water, quantity sutficient for 4 cc. (3) Injectable preparation 500:

Tetracycline hexylsulfamate g 0.650 Sodium glycinate g 0.200 NaHSO g 0.030 Ampoule Lidocaine hydrochloride g 0.050 Propylene glycol g 0.300 Polysorbate 80 g 0.180 H O, quantity suflicient for 5 cc. (4) Suppositories:

Tetracycline hexylsulfamate g 0.163 Massa estearinum, quantity sufi'icient for 1 suppository. (5) Suppositories:

Tetracycline hexylsulfamate g 0.325

Messa estearinum, quantity suflicient for 1 suppository.

10 6) Capsules:

Tetracycline hexylsulfamate g 0.325 Magnesium stearate g 0.020 Amidon g 0.080 (7) Extemporaneous syrup:

Powder- Tetracycline hexylsulfamate g 0.033 Ascorbic acid g 0.005 Sodium tartrate g 0.050 Sodium cyclamate g 0.020 Saccharine soluble g 0.002 Methylcellulose g 0.010 Solution:

Simple 50% syrup cc 0.3

H 0, quantity sufiicient for 1 cc.

The tetracycline derivatives of the present invention may also be manufactured in the form of compressed pills, drages, syrups in an already mixed solution or suspension, drops and other forms of local or general usage. The injectable preparations thereof may also be prepared in the form of an already mixed solution.

It is apparent from the foregoing tests that the novel compounds according to the present invention may be utilized with beneficial results in human therapy.

In the general formula given hereinabove for the compounds of the present invention, it is to be understood that T represents a tetracycline molecule or a molecule of any therapeutically administrable derivative thereof and is not limited to those specifically above. Therapeutic tetracycline molecules are known in the art, and the sulfamate derivatives thereof of the present invention are all therapeutically beneficial and have an excellent local tolerance for all methods of administration. The tetracycline moiety is attached to the (R-NHSO;,H) moiety by a salt-like bond. The R is a linear alkyl radical of 2 to 18 carbon atoms and includes, for example, the alkyl groups ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl. And, as noted above, n may be either 1 or 2. All of these derivatives show the beneficial properties illustrated by tetracycline dodecylsulfamate and tetracycline hexylsulfamate hereinabove.

The invention being thus described, it will be obvious that the same may be varied in many Ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included herein.

We claim:

1. A compound of the formula:

T- (RNHSO H) wherein T is selected from the group consisting of tetracycline, oxytetracycline, chlortetracycline, demethylchlortetracycline, methyleneoxytetracycline, N (2 hydroxy ethyl) diethylenediaminomethylenetetracycline, pyrrolidinomethylenetetracycline and tetracycline-L-methylene lysine, R is a linear alkyl group of 10 to 18 carbon atoms and n is 1 or 2.

2. A compound according to claim 1, wherein n is 1.

3. A compound according to claim 1, wherein n. is 2.

4. Tetracycline n-dodecylsulfamate.

5. A compound according to claim 1, wherein R is ndodecyl.

6. A compound according to claim 1, wherein R is nhexadecyl.

References Cited UNITED STATES PATENTS 3,299,124 1/ 1967 Boissier et a1.

ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US. Cl. X.R. 260-268, 326.3, 519; 424227 

